Successful development of a vaccine against HIV will likely require the induction of both antibody and/or cellular immune responses sufficient to prevent infection or disease respectively following infectious challenge. While the induction of antibody responses for a variety of other infectious pathogens is readily achieved by a variety of vaccine formulations, live attenuated, recombinant viral vaccines or plasmid DNA vaccines only induce the induction of long-lived cellular immune responses, particularly CD8+ T cell responses. Moreover, since live attenuated HIV vaccines might be precluded from use due to safety concerns and DNA vaccines at present only induce modest CD8+ T cell responses in humans, there is an urgent need to develop ways to enhance the generation and maintenance of CD8+ T cell responses in humans in following immunization. This study focuses on how to optimize the magnitude and duration of CD8+ T cell responses following vaccination in rodents and primates using a variety of vaccine formulations. The data obtained over this past year have shown the following; 1. A comparative analysis of single or combination TLR ligands was done in NHP using SIV Gag protein and an oil/water emulsion. Amongst the adjuvants used, Poly IC and a TLR 7/8 agonist were the most potent for inducing SIV Gag specific CD4 and CD8+ T cell responses. 2. A non-human primate study showed that a non-targeted and targeted HIV Gag protein to DEC-205, a receptor specific for dendritic cells induced potent and comparable Th1 immunity following a series of immunizations. However the protein vaccine elicited higher avidity antibody responses while the DEC-205 targeted vaccine had higher CD8+ T cell responses. These data show that delivery of protein with Poly ICLC as an adjuvant can influence the type of adaptive immunity generated. Animals have been boosted with a pox viral vector encoding HIV Gag and the immune responses will be assessed. 3. A comparative analysis of adjuvants and formulation was recently initiated in NHP using HIV Env protein. This study focused on two clinically approved adjuvants ( alum and MF-59) with or without TLR 4 or TLR 7 ligands as additional immune stimulators. Based on our other studies, we also included a group with Poly ICLC as an adjuvant. An extensive analysis will be assessed to understand the mechanisms by which the adjuvants and formulations influence the magnitude, quality and durability of the HIV Env specific antibody responses. 4. A comparative analysis of adenoviral or pox viral vectors encoding SIV Gag was initiated this year. This study should provide insight into the mechanisms by which these vectors mediate antibody and T cell immunity.